scholarly journals Drug Resistance in Non-Hodgkin Lymphomas

2020 ◽  
Vol 21 (6) ◽  
pp. 2081 ◽  
Author(s):  
Pavel Klener ◽  
Magdalena Klanova
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Front Line ◽  
Mechanisms Of Resistance ◽  
Treatment Algorithms ◽  
Acquired Drug Resistance ◽  
Complex Process ◽  
Medical Need ◽  
Druggable Targets

Non-Hodgkin lymphomas (NHL) are lymphoid tumors that arise by a complex process of malignant transformation of mature lymphocytes during various stages of differentiation. The WHO classification of NHL recognizes more than 90 nosological units with peculiar pathophysiology and prognosis. Since the end of the 20th century, our increasing knowledge of the molecular biology of lymphoma subtypes led to the identification of novel druggable targets and subsequent testing and clinical approval of novel anti-lymphoma agents, which translated into significant improvement of patients’ outcome. Despite immense progress, our effort to control or even eradicate malignant lymphoma clones has been frequently hampered by the development of drug resistance with ensuing unmet medical need to cope with relapsed or treatment-refractory disease. A better understanding of the molecular mechanisms that underlie inherent or acquired drug resistance might lead to the design of more effective front-line treatment algorithms based on reliable predictive markers or personalized salvage therapy, tailored to overcome resistant clones, by targeting weak spots of lymphoma cells resistant to previous line(s) of therapy. This review focuses on the history and recent advances in our understanding of molecular mechanisms of resistance to genotoxic and targeted agents used in clinical practice for the therapy of NHL.

scholarly journals Acquired Resistance to Clinical Cancer Therapy: A Twist in Physiological Signaling

2016 ◽  
Vol 96 (3) ◽  
pp. 805-829 ◽  
Author(s):  
Andreas Wicki ◽  
Mario Mandalà ◽  
Daniela Massi ◽  
Daniela Taverna ◽  
Huifang Tang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Immune System ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Therapeutic Strategies ◽  
Host Immune System ◽  
Cancer Therapies ◽  
Acquired Drug Resistance ◽  
Physiological Signal

Although modern therapeutic strategies have brought significant progress to cancer care in the last 30 years, drug resistance to targeted monotherapies has emerged as a major challenge. Aberrant regulation of multiple physiological signaling pathways indispensable for developmental and metabolic homeostasis, such as hyperactivation of pro-survival signaling axes, loss of suppressive regulations, and impaired functionalities of the immune system, have been extensively investigated aiming to understand the diversity of molecular mechanisms that underlie cancer development and progression. In this review, we intend to discuss the molecular mechanisms of how conventional physiological signal transduction confers to acquired drug resistance in cancer patients. We will particularly focus on protooncogenic receptor kinase inhibition-elicited tumor cell adaptation through two major core downstream signaling cascades, the PI3K/Akt and MAPK pathways. These pathways are crucial for cell growth and differentiation and are frequently hyperactivated during tumorigenesis. In addition, we also emphasize the emerging roles of the deregulated host immune system that may actively promote cancer progression and attenuate immunosurveillance in cancer therapies. Understanding these mechanisms may help to develop more effective therapeutic strategies that are able to keep the tumor in check and even possibly turn cancer into a chronic disease.

scholarly journals Pancreatic Neuroendocrine Tumors: Molecular Mechanisms and Therapeutic Targets

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5117
Author(s):  
Chandra K. Maharjan ◽  
Po Hien Ear ◽  
Catherine G. Tran ◽  
James R. Howe ◽  
Chandrikha Chandrasekharan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Neuroendocrine Tumors ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Somatostatin Receptor ◽  
Therapeutic Targets ◽  
Model Systems ◽  
Pancreatic Neuroendocrine Tumors ◽  
Acquired Drug Resistance ◽  
Molecular Alterations

Pancreatic neuroendocrine tumors (pNETs) are unique, slow-growing malignancies whose molecular pathogenesis is incompletely understood. With rising incidence of pNETs over the last four decades, larger and more comprehensive ‘omic’ analyses of patient tumors have led to a clearer picture of the pNET genomic landscape and transcriptional profiles for both primary and metastatic lesions. In pNET patients with advanced disease, those insights have guided the use of targeted therapies that inhibit activated mTOR and receptor tyrosine kinase (RTK) pathways or stimulate somatostatin receptor signaling. Such treatments have significantly benefited patients, but intrinsic or acquired drug resistance in the tumors remains a major problem that leaves few to no effective treatment options for advanced cases. This demands a better understanding of essential molecular and biological events underlying pNET growth, metastasis, and drug resistance. This review examines the known molecular alterations associated with pNET pathogenesis, identifying which changes may be drivers of the disease and, as such, relevant therapeutic targets. We also highlight areas that warrant further investigation at the biological level and discuss available model systems for pNET research. The paucity of pNET models has hampered research efforts over the years, although recently developed cell line, animal, patient-derived xenograft, and patient-derived organoid models have significantly expanded the available platforms for pNET investigations. Advancements in pNET research and understanding are expected to guide improved patient treatments.

Whole-genome sequencing differentiates relapse from re-infection in TB

2021 ◽  
Vol 25 (12) ◽  
pp. 995-1000
Author(s):  
A. Nikolenka ◽  
M. Mansjö ◽  
A. Skrahina ◽  
H. Hurevich ◽  
V. Grankov ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Treatment Failure ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Drug Susceptibility ◽  
Whole Genome ◽  
Single Nucleotide ◽  
Acquired Drug Resistance ◽  
Resistant Strains

BACKGROUND: Distinguishing TB relapse from re-infection is important from a clinical perspective to document transmission patterns. We investigated isolates from patients classified as relapse to understand if these were true relapses or re-infections. We also investigated shifts in drug susceptibility patterns to distinguish acquired drug resistance from re-infection with resistant strains.METHODS: Isolates from pulmonary TB patients from 2009 to 2017 were analysed using whole-genome sequencing (WGS).RESULTS: Of 11 patients reported as relapses, WGS results indicated that 4 were true relapses (single nucleotide polymorphism difference ≤5), 3 were re-infections with new strains, 3 were both relapse and re-infection and 1 was a suspected relapse who was later categorised as treatment failure based on sequencing. Of the 9 patients who went from a fully susceptible to a resistant profile, WGS showed that none had acquired drug resistance; 6 were re-infected with new resistant strains, 1 was probably infected by at least two different genotype strains and 2 were phenotypically misclassified.CONCLUSIONS: WGS was shown to distinguish between relapse and re-infection in an unbiased way. The use of WGS minimises the risk of false classification of treatment failure instead of re-infection. Furthermore, our study showed that strains without major genetic differences can cause re-infection.

scholarly journals Nanomedicine Strategies for Management of Drug Resistance in Lung Cancer

2022 ◽  
Author(s):  
Mohamed Haider ◽  
Amr El Sherbeny ◽  
Valeria Pittalà ◽  
Antonino N. Fallica ◽  
Maha Ali Alghamdi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Therapeutic Agents ◽  
Future Directions ◽  
Significant Challenge ◽  
Cancer Occurrence ◽  
Complex Process ◽  
Anticancer Treatment ◽  
Therapeutic Alternatives

Lung cancer (LC) is one of the leading causes of cancer occurrence and mortality worldwide. Treatment of patients with advanced and metastatic LC presents a significant challenge as malignant cells use different mechanisms to resist chemotherapy. Drug resistance (DR) is a complex process that occurs due to a variety of genetic and acquired factors. Identifying the mechanisms underlying DR in LC patients and possible therapeutic alternatives for more efficient therapy is a central goal of LC research. Advances in nanotechnology resulted in the development of targeted and multifunctional nanoscale drug constructs. The possible modulation of the components of nanomedicine, their surface functionalization, and encapsulation of various active therapeutics provide promising tools to bypass crucial biological barriers. These attributes enhance the delivery of multiple therapeutic agents directly to the tumor microenvironment (TME), resulting in reversal of LC resistance to anticancer treatment. This review provides a broad framework for understanding the different molecular mechanisms of DR in lung cancer; presents novel nanomedicine therapeutics aimed to improve the efficacy of treatment of various forms of resistant LC; outlines current challenges in using nanotechnology for reversing DR; and discusses the future directions for clinical application of nanomedicine in management of LC resistance.

scholarly journals Kinome rewiring during acquired drug resistance in neuroendocrine neoplasms

2021 ◽  
Vol 28 (1) ◽  
pp. 39-51
Author(s):  
Corinne Gérard ◽  
Marie Lagarde ◽  
Flora Poizat ◽  
Sandrine Oziel-Taieb ◽  
Vincent Garcia ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Significant Rise ◽  
Neuroendocrine Neoplasms ◽  
Drug Resistant ◽  
Acquired Drug Resistance ◽  
Viability Assay ◽  
Novel Therapeutic Strategies ◽  
Resistant Cells

Although there is evidence of a significant rise of neuroendocrine neoplasms (NENs) incidence, current treatments are largely insufficient due to somewhat poor knowledge of these tumours. Despite showing differentiated features, NENs exhibit therapeutic resistance to most common treatments, similar to other cancers in many instances. Molecular mechanisms responsible for this resistance phenomenon are badly understood. We aimed at identifying signalling partners responsible of acquired resistance to treatments in order to develop novel therapeutic strategies. We engineered QGP-1 cells resistant to current leading treatments, the chemotherapeutic agent oxaliplatin and the mTor inhibitor everolimus. Cells were chronically exposed to the drugs and assessed for acquired resistance by viability assay. We used microarray-based kinomics to obtain highthroughput kinase activity profiles from drug sensitive vs resistant cells and identified ‘hit’ kinases hyperactivated in drug-resistant cells, including kinases from FGFR family, cyclin-dependant kinases and PKCs in oxaliplatin-resistant (R-Ox) QGP-1 cells. We then validated these ‘hit’ kinases and observed that ERK signalling is specifically enhanced in QGP-1 R-Ox cells. Finally, we assessed drug-resistant cells sensitivity to pharmacological inhibition of ‘hit’ kinases or their signalling partners. We found that FGFR inhibition markedly decreased ERK signalling and cell viability in QGP-1 R-Ox cells. These results suggest that the FGFR/ERK axis is hyperactivated in response to oxaliplatin-based chemotherapeutic strategy. Thus, this sensitive approach, based on the study of kinome activity, allows identifying potential candidates involved in drug resistance in NENs and may be used to broadly investigate markers of NENs therapeutic response.

Molecular mechanisms of resistance to anti-angiogenic drugs

2020 ◽  
Author(s):  
Arianna Filippelli ◽  
Valerio Ciccone ◽  
Sandra Donnini ◽  
Lucia Morbidelli
Keyword(s):  
Molecular Mechanisms ◽  
Mechanisms Of Resistance

E6 and E7 oncoproteins: Potential targets of cervical cancer

2020 ◽  
Vol 27 ◽  
Author(s):  
Ramarao Malla ◽  
Mohammad Amjad Kamal
Keyword(s):  
Cervical Cancer ◽  
Drug Resistance ◽  
Host Cell ◽  
Molecular Mechanisms ◽  
Immune Therapy ◽  
Cervical Lesions ◽  
Diagnostic Strategies ◽  
E6 And E7 Oncoproteins ◽  
E6 And E7

: Cervical cancer (CC) is the fourth leading cancer in women in the age group 15-44 globally. Experimental as well as epidemiological studies identified that type16 and 18 HPV cause 70% of precancerous cervical lesions as well as cervical cancer worldwide by bringing about genetic as well as epigenetic changes in the host genome. The insertion of the HPV genome triggers various defense mechanisms including the silencing of tumor suppressor genes as well as activation of oncogenes associated with cancer metastatic pathway. E6 and E7 are small oncoproteins consisting of 150 and 100 amino acids respectively. These oncoproteins affect the regulation of the host cell cycle by interfering with p53 and pRb. Further these oncoproteins adversely affect the normal functions of the host cell by binding to their signaling proteins. Recent studies demonstrated that E6 and E7 oncoproteins are potential targets for CC. Therefore, this review discusses the role of E6 and E7 oncoproteins in metastasis and drug resistance as well as their regulation, early oncogene mediated signaling pathways. This review also uncovers the recent updates on molecular mechanisms of E6 and E7 mediated phytotherapy, gene therapy, immune therapy, and vaccine strategies as well as diagnosis through precision testing. Therefore, understanding the potential role of E6/E7 in metastasis and drug resistance along with targeted treatment, vaccine, and precision diagnostic strategies could be useful for the prevention and treatment of cervical cancer.

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